Magnetic resonance (MR) is widely used for obtaining spatial images of multi-celled organisms or bodies for clinical diagnosis. A review of this technology and clinical applications is provided by D. P. Swanson et al, in Pharmaceuticals in Medical Imagina, 1990, Macmillan Publishing Company, pages 645-681.
Magnetic resonance images are derived instrumentally as a composite of the effects of a number of parameters which are analyzed and combined by computer. Choice of the appropriate instrument parameter controls, such as radio frequency (Rf), pulsation and timing can be utilized to enhance or attenuate the signals of any of the image-producing parameters to thereby improve image quality and provide better anatomical and functional information. In many cases, magnetic resonance imaging has proven to be a valuable diagnostic tool, inasmuch as normal and diseased tissue, by virtue of their possessing different responses to parameter values, can be differentiated in the image.
In magnetic resonance imaging of the body of a mammal such as a human, an in vivo image of an organ or tissue is obtained by placing at least the portion of the body to be imaged in a strong external magnetic field, pulsing with radio frequency energy, and observing the effect of the pulses on the magnetic properties of the protons contained in and surrounding the organ or tissue. This is especially useful in imaging the circulatory vasculation of the body (i.e. the blood pool). A number of magnetic parameters can be measured. The proton relaxation times, T.sub.1 and T.sub.2, are of primary importance. T.sub.1, also called the spin-lattice or longitudinal relaxation time, and T.sub.2, also called the spin-spin or transverse relaxation time, are functions of the chemical and physical environment of the organ or tissue water and are measured using Rf pulsing techniques. This information is analyzed as a function of spatial location by computer which transforms the information to generate an image.
Often the image produced lacks appropriate contrast, e.g., between normal and diseased tissue, reducing diagnostic effectiveness. To overcome this drawback, contrast agents have been used. MR contrast agents are magnetically active substances which exert an effect on the magnetic resonance parameters of nuclei in molecules proximal to them. Theoretically, a contrast agent, if taken up preferentially by a certain portion of an organ or a certain type of tissue, e.g., diseased tissue, can provide a change in contrast or enhancement in the resultant images of that tissue.
Inasmuch as magnetic resonance images are strongly affected by variations in the T.sub.1 and T.sub.2 parameters, it is desirable to have a contrast agent which effects either or both parameters. Research has focused predominantly on two classes of magnetically active materials, i.e., paramagnetic materials, which act to decrease T.sub.1, and T.sub.2, and superparamagnetic materials, which act primarily to decrease T.sub.2. At low concentrations, paramagnetic materials effect T.sub.1 more than T.sub.2.
Paramagnetism occurs in materials that contain electrons with unpaired spins. Paramagnetic materials are characterized by a weak magnetic susceptibility (response to an applied magnetic field). Paramagnetic materials become weakly magnetic in the presence of a magnetic field and rapidly lose such activity, i.e., demagnetize, once the external field has been removed. It has long been recognized that the addition of paramagnetic materials to water causes a decrease in the T.sub.1 parameter of the hydrogen nuclei.
Paramagnetic materials, for example, comprising the paramagnetic lanthanides, especially materials containing Gd.sup.+3 have been used as magnetic resonance contrast agents primarily because of their effect on T.sub.1. Gd.sup.+3 has seven unpaired electrons in its 4f orbitals and exhibits the greatest longitudinal relaxivity of any element.
A major concern with the use of contrast agents for magnetic resonance imaging is that at magnetically effective doses many paramagnetic materials exert toxic effects on biological systems making them inappropriate for in vivo use. For example, the free solubilized form of Gd.sup.+3 salts are quite toxic. To make the gadolinium ion more suitable for in vivo use, researchers have chelated it using diethylenetriaminepentaacetic acid (DTPA). This agent, Gd-DTPA, has been successful in enhancing magnetic resonance images of human brain and renal tumors.
Despite its satisfactory relaxivity and safety, this formulation has several disadvantages. For example, due to its low molecular weight, Gd-DTPA is cleared very rapidly from the blood stream and tissue lesions (tumors). This limits the imaging window, the number of optimally enhanced images that can be obtained after each injection, and increases the agent's required dose and its toxic effects. In addition, the biodistribution of Gd-DTPA is suboptimal for imaging body tumors and infections due to its low molecular weight.
Several approaches have been taken in attempts to overcome these disadvantages. For example, Gd.sup.+3 and Gd.sup.+3 -chelates have been chemically conjugated to proteins such as albumin, polylysines and immunoglobulins. Drawbacks of conjugating DTPA to protein carriers for use in magnetic resonance image enhancement include inappropriate biodistribution and toxicity. In addition, proteins provided are not subject to wide synthetic variation. Additionally, thermal sterilization of protein conjugates tends to be problematic, especially in the case of albumin conjugates. Also proteins are metabolized by the body, providing an imaging agent which changes molecular weight uncontrollably. This disadvantage causes blood pool half-life tissue specificity of the imaging agent to change continuously. Proteins are immunogenic substances, which have several known drawbacks for therapeutic or diagnostic use. Solutions to these recognized problems are of importance in the areas of magnetic resonance, x-ray and fluorescence imaging.
It is apparent that it would be desirable to provide new classes of magnetic resonance contrast enhancing agents, having a specificity toward accumulation in different tissues, and which remain in the blood pool for long periods of time.
The importance of drug targeting has been recognized in recent years, especially for anticancer drugs, inasmuch as toxicity to normal cells is often dose limiting. Drug targeting has been employed in this area, using antibodies to tumor associated antigens or using other proteins and saccharides to avoid the random destruction of healthy tissue. Antibodies and portions or fragments thereof have been most widely used due to their specificity. The current approaches, however, are expensive and pose immunogenicity problems. Furthermore, not all cancers are susceptible to drug therapy.
Certain tumors are especially susceptible to treatment by radiation, such as those of hematopoietic origin, for example, leukemias and lymphomas; others are less susceptible to such treatment such as adenocarcinomas of the head and neck, or breast, ovarian, cervical or rectal adenocarcinomas. However, certain of these cancers cannot be treated by externally derived beam radiation as a practical matter because of the location of the tumor and the effect of such radiation on surrounding healthy tissue. Hence, it is advantageous to deliver a source of radiation such as a radio active isotope to the tumor, while minimizing damage to surrounding healthy tissues which in conventional treatment would likely lie in the path of the beam. It would be advantageous to deliver the appropriate radiation dosage directly to the tumor with significantly less harm to the surrounding tissue thereby increasing the therapeutic ratio (the ratio of damage to the tumor divided by damage to the most sensitive healthy tissue).
In summary, it would be advantageous to prepare a material that would overcome the following disadvantages; 1) toxicity, 2) short blood pool residence time, 3) lack of specificity for tissues which are to be targeted, 4) immunogenicity, and 5) uncontrolled metabolism of the polymer. The art records attempts at providing such a polymer.
Felder et al, U.S. Pat. No. 4,916,246 describe low molecular weight paramagnetic chelates stated to be useful for NMR imaging having the formula: ##STR2## wherein Me is Fe, Mn, Dy or Gd, Z is H or a negative charge, R.sub.1 and R.sub.2 are substituted alkyl and R can be poly(oxy-alkyl) with 1 to 50 oxygen atoms and from 3 to 150 carbon atoms.
U.S. Pat. No. 5,137,711 describes low molecular weight complexes of paramagnetic ions with derivatives of DTPA or EDTA represented by the formula: ##STR3## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR4## and M.sup.+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of +2 or +3; the R.sup.1 and R groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR5## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is H, alkyl having 1 to 8 carbon atoms (i.e. C.sub.1 -C.sub.8) or aryl, unsubstituted or substituted with hydroxy, and R.sup.3 is H, R.sup.2, alkyl having from 1 to 8 carbon atoms, hydroxy, alkoxy having 1-8 carbon atoms, cycloalkyl with up to 10 carbon atoms or an aryl group which is optionally substituted with hydroxy, carboxy, halide, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms, wherein 2 of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are groups ##STR6##
Application WO 91-18630 (no English equivalents available) describes substances for treating or diagnosing tumors, having at least one aliphatic amino group, or at least one phenolic hydroxyl and/or amino group and at least one aliphatic amino group, all substituted with polyethylene glycol chains, whose degree of polymerization, n, is 5 to 250. The terminal hydroxyl group of the chain is substituted by C.sub.1 -C.sub.12 alkyl ester.
Herz, et al., U.S. Pat. No. 3,859,337 describes low molecular weight ethylenediamine tetraacetic acid anhydride derivatives useful as chelating agents.